title: Role of Myc in hepatocellular proliferation and hepatocarcinogenesis.
abstract: OBJECTIVE
  Myc is involved in cell growth, proliferation, apoptosis, energy metabolism, and differentiation. Whether it is essential for hepatocellular proliferation and carcinogenesis is unclear due to a lack of an efficient hepatocyte-specific Myc disruption model. This study used a novel genetic model to investigate the involvement of Myc in hepatocellular proliferation and hepatocarcinogenesis in mice.
  
  
  METHODS
  Temporal hepatocyte-specific Myc disruption was achieved by use of the tamoxifen-inducible Cre-ER(T2) recombinase system under control of the serum albumin promoter. Hepatocyte proliferation was assessed by administering peroxisome proliferator-activated receptor α (PPARα) agonist Wy-14,643. A diethylnitrosamine-induced liver cancer model was used to evaluate the role of Myc in hepatocarcinogenesis.
  
  
  RESULTS
  Tamoxifen administration induced recombination of Myc specifically in hepatocytes of Myc(fl/fl,ERT2-Cre) mice. When treated with a known hepatocellular proliferative stimulus Wy-14,643, Myc(fl/fl,ERT2-Cre) mice showed a lower liver/body weight ratio and suppressed hepatocyte proliferation as compared to Myc(fl/fl) mice. Hepatic expression of cell cycle control genes, DNA repair genes, and Myc target gene miRNAs were upregulated in Wy-14,643-treated Myc(fl/fl) mouse livers, but not in Wy-14,643-treated Myc(fl/fl,ERT2-Cre) livers. However, no differences were observed in the lipid-lowering effect of Wy-14,643 between Myc(fl/fl,ERT2-Cre) and Myc(fl/fl) mice, consistent with no differences in the expression of several PPARα target genes involved in fatty acid β-oxidation. Moreover, when subjected to the diethylnitrosamine liver cancer bioassay, Myc(fl/fl,ERT2-Cre) mice exhibited a markedly lower incidence of tumor formation compared with Myc(fl/fl) mice.
  
  
  CONCLUSIONS
  Myc plays an essential role in hepatocellular proliferation and liver tumorigenesis.
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States.
authors.forename: Aijuan
authors.initials: A
authors.lastname: Qu
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States.
authors.forename: Changtao
authors.initials: C
authors.lastname: Jiang
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States.
authors.forename: Yan
authors.initials: Y
authors.lastname: Cai
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States.
authors.forename: Jung-Hwan
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States.
authors.forename: Naoki
authors.initials: N
authors.lastname: Tanaka
authors.affiliation: Global VetPathology, Montgomery Village, MD 20866, United States.
authors.forename: Jerrold M
authors.initials: JM
authors.lastname: Ward
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States; Department of Molecular and Integrative Physiology and Internal Medicine, Division of Gastroenterology, University of Michigan School of Medicine, Ann Arbor, MI 48109, United States.
authors.forename: Yatrik M
authors.initials: YM
authors.lastname: Shah
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States. Electronic address: gonzalef@mail.nih.gov.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D005227:Fatty Acids / Q000378:metabolism; D055786:Gene Knockout Techniques; D016259:Genes, myc; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D008114:Liver Neoplasms, Experimental / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D008957:Models, Genetic; D047493:PPAR alpha / Q000819:agonists; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D005227:Fatty Acids; C575895:MIRN17-92 microRNA, mouse; D035683:MicroRNAs; D047493:PPAR alpha; D011743:Pyrimidines; D012333:RNA, Messenger; C006253:pirinixic acid
keywords: Acox1; BrdU; CDK; Cell cycle control; Cell proliferation; Chek1; Cre-ER(T2); Cyp4a10 and Cyp4a14; DEN; Mcm; Myc; Myc(fl/fl); Myc(fl/fl)Mx-Cre; Myc(fl/fl,ERT2-Cre); PPARα; RAD51 homolog (S. cerevisiae); Rad51; SA; Tumorigenesis; acyl-CoA oxidase; bHLH; basic helix-loop-helix leucine zipper; bromodeoxyuridine; checkpoint kinase 1 homologue; cre recombinase, tamoxifen-inducible estrogen receptor ligand-binding domain fusion protein; cyclin-dependent kinase; cytochromes P450 4a10 and 4a14; diethynitrosamine; floxed Myc allele; inducible liver-specific Myc knockout mouse; minichromosome maintenance; peroxisome proliferator-activated receptor α; serum albumin promoter; α/β interferon-inducible Mx-promoter driving Cre recombinase